Celiac disease (CD) is an autoimmune response to gluten proteins that affects 3M people in the US and 50M worldwide. These proteins incite an inflammatory reaction that eventually destroys the absorptive villi in the duodenum, resulting in gastrointestinal symptoms, malabsorption, malnutrition, and an increased incidence of other autoimmune diseases, diabetes, and cancer. A definitive diagnosis of CD is made by random endoscopic biopsy with microscopic findings of cellular and architectural changes in the duodenal mucosa. CD can be effectively cured by adherence to a gluten free diet (GFD). Since a GFD is a lifelong commitment that is expensive, difficult to comply with, and can have psychosocial implications, the vast majority of patients are not placed on this regimen unless they have biopsy-confirmed disease. Duodenal endoscopic biopsy is a poor gold standard that suffers from many flaws. Because endoscopic biopsy typically requires sedation, the procedures are expensive and can be difficult to tolerate. Random duodenal biopsy also only samples a very small portion of the duodenal wall. Since the disease is often patchy, it is very common for those with the disease to have multiple negative biopsy results. Tissue processing artifacts and lack of standards for acquiring and interpreting the biopsies also contribute to diagnostic uncertainty. To a large part, these problems with endoscopic biopsy have led to massive delays and underdiagnosis of CD in the population. This problem must be solved because untreated CD is associated with a 2-4x increase in mortality, the cost of which exceeds $30B/year in the US. We have developed a new technology called tethered capsule endomicroscopy (TCE) that overcomes the limitations of endoscopic biopsy. TCE involves swallowing an optomechanically-engineered pill that captures three-dimensional microscopic images of the gastrointestinal (GI) tract as it descends via peristalsis. Our first results with this technology demonstrated that the microstructure of the entire esophagus can be imaged in just a few minutes in a simple, rapid, and painless procedure. In this proposal, we will advance TCE technology further so that it is optimized for imaging the entire duodenum and diagnosing CD. The new device, termed multimodality TCE (MM-TCE) will incorporate multiple imaging modalities that are specifically designed for CD diagnosis in vivo: 1) optical coherence tomography (OCT) for imaging the depth-dependent architectural changes such as duodenal blunting, 2) SECM for visualizing the lymphocytic infiltrate in the epithelium, and 3) video imaging so that the device can be quickly navigated through the stomach into the duodenum. Once the MM-TCE system and device has been constructed, clinical validation studies will be conducted to determine the accuracy of this device compared to corresponding histology and the diagnostic yield relative to endoscopic duodenal biopsy. The end product of this research will be a swallowable capsule microscope that avoids sampling error by imaging the entire duodenum, is less expensive, and better tolerated than the current standard of care. Beyond its immediate clinical impact for CD, this capsule technology will also transform how we obtain microscopic tissue diagnoses for other disorders of the upper GI tract.